Alzheimer's disease (AD) is one of the major health problems in this country and affects over 4.5 million persons. The key to the disease is understanding the pathogenesis of neuron degeneration in specific brain regions so that treatment and prevention can be based on solid data. This application is a resubmission of a competitive renewal of the program project, "Beta-Amyloid and Oxidative Stress in AD" (P01 AG05119-20) by the Sanders-Brown Center on Aging at the University of Kentucky (UK). Abundant evidence indicates that free radical mediated oxidative damage in the brain is prominent in AD, especially in the earliest detectable clinical phase of AD - mild cognitive impairment (MCI). The major hypothesis of this application is that beta amyloid peptide (AB) is one of the pivotal mechanisms in oxidative stress/damage to neurons in AD. The proposal consists of three cores including 1) an Administrative Core that provides supervision, fiscal management, biostatistical support and database management, clinical and neuropathological data, and brain specimens from the UK AD Center, 2) a unique Beta-Amyloid Core that will provide the AB index (total AB{1-40} and AB{1-42}, AB solubility, oligomeric and fibrillar AB quantitation and plaque quantitation) from human subjects and transgenic mice and also will provide toxic assembled AB and non-toxic scrambled AB for cell culture experiments, and 3) an Animal Core that will supply APP/PS1 knock-in mutant mice and WT mice, and primary rodent cortical neuron cultures for projects. Each project uses short postmortem brain specimens from longitudinally followed preclinical AD (PCAD), MCI, late AD, normal controls and frontotemporal dementia (as a disease control) subjects, APP/PS1 transgenic mice and cell cultures, and each has a therapeutic component and excellent preliminary data to support their hypotheses. Project 1 examines the hypothesis that brain RNA oxidation is an early event in AD and is mediated, at least in part, by Ap and that the RNA oxidation impairs protein synthesis and contributes to neuron dysfunction. Project 2 examines the hypothesis that AB-mediated oxidative modifications of and subsequent dysfunction of Pin1 are fundamental to the genesis of specific pathological features in AD. Project 3 will examine the hypothesis that elevations in RAGE-ligand interactions occur in AD, with soluble RAGE modulating Ap assembly and toxicity. Project 4 examines the hypothesis that sustained activation of NADPH oxidase by toxic forms of AB triggers a cascade linking increased ROS to altered redox-based signaling and neurotoxic oxidative damage. This well integrated program project will move the field of AB and oxidative stress in AD forward and gain insights into mechanisms of neuron degeneration so that successful interventions can be developed to treat or prevent the most dehumanizing disorder to affect humans.